A single intravenous infusion of DMT, a fast-acting psychedelic compound found in the Amazonian brew ayahuasca, significantly reduced depression symptoms in adults with major depressive disorder, according to a phase IIa clinical trial published in Nature Medicine. The randomized, double-blind study tested a 21.5 mg dose of SPL026, a pharmaceutical-grade DMT fumarate, delivered over just 10 minutes alongside supportive psychotherapy. The results mark the first placebo-controlled evidence that a short-acting psychedelic can produce meaningful antidepressant effects within two weeks, a timeline that could reshape how clinicians think about treatment-resistant depression.
What the Trial Tested and Found
The study enrolled adults diagnosed with moderate-to-severe major depressive disorder and randomly assigned them to receive either 21.5 mg of intravenous SPL026 or a matched placebo. Both groups also received supportive psychotherapy sessions surrounding the infusion. The trial’s primary efficacy measure was the change in Montgomery-Åsberg Depression Rating Scale, or MADRS, scores at two weeks, a standard clinical benchmark for gauging depression severity. The phase IIa report showed a statistically significant separation between the DMT and placebo arms on that measure, with the drug group experiencing substantially greater symptom relief.
The registration entry on ClinicalTrials.gov confirms the study was designed as a two-part investigation: the first part assessed safety and dosing in healthy volunteers, and the second tested efficacy in patients with depression. The protocol allowed up to two infusions spaced two weeks apart, with participants who initially received placebo eligible for an open-label active dose in a second phase. This placebo-active versus active-active structure gave researchers a way to observe both blinded and unblinded responses while maintaining ethical standards that ensured all participants could eventually access the experimental treatment.
Why a 10-Minute Infusion Changes the Calculus
Most psychedelic-assisted therapy protocols under clinical investigation require patients to spend six to eight hours in a supervised setting. Psilocybin trials, for instance, typically administer a 25 mg oral capsule that produces effects lasting several hours, as illustrated by a separate investigation in treatment-resistant depression. DMT’s pharmacology is fundamentally different. Delivered intravenously, its psychoactive window is compressed into roughly 20 minutes, and the 10-minute infusion protocol used in this trial was specifically engineered to manage the intensity of the experience while keeping the total clinical encounter far shorter than competing approaches.
That brevity has practical consequences for any future rollout. A treatment that fits inside a standard outpatient appointment slot, rather than consuming most of a clinical day, could be staffed and scheduled using existing psychiatric infrastructure. Independent psychiatrists have noted that the short session length is one of the most commercially and clinically relevant features of DMT-assisted therapy, because it lowers the per-patient cost of supervision and could make psychedelic treatment accessible to health systems that lack the resources for daylong monitoring. The question is whether the compressed experience delivers equivalent long-term benefit, a comparison no head-to-head trial has yet tested, and which will require larger studies with extended follow-up periods.
How the Dose Was Chosen and Validated
The 21.5 mg dose did not emerge arbitrarily. A prior phase I safety study in healthy participants systematically escalated doses and characterized the pharmacokinetics and pharmacodynamics of SPL026. That earlier work used a two-phase infusion protocol over 10 minutes, measuring acute subjective effects through validated instruments including intensity scales and mystical-type experience questionnaires. The 21.5 mg level was selected because it reliably produced strong psychedelic effects while remaining well tolerated, with no serious adverse events reported in the healthy volunteer cohort.
Carrying that safety profile forward into the depression trial was a deliberate de-risking strategy. The Nature Medicine paper reports both primary and secondary endpoint data alongside a detailed safety analysis, confirming that the tolerability observed in healthy subjects held up in a psychiatric population. Transient cardiovascular changes and the expected perceptual distortions were documented, but the overall adverse-event profile did not raise new red flags. For a compound that produces intense hallucinations, even briefly, that safety record is a prerequisite for regulators considering whether to greenlight larger, phase III trials that would move SPL026 closer to potential approval.
Blinding Problems and Interpretive Limits
The most persistent criticism of psychedelic trials applies here as well: it is extremely difficult to blind participants to whether they received a powerful hallucinogen or an inert placebo. Anyone who experiences vivid visual and emotional distortions within minutes of an infusion can reasonably guess they received the active drug, and that awareness can inflate self-reported improvement through expectancy effects. Independent psychiatrists have flagged this blinding limitation as a significant interpretive caveat, one that no psychedelic trial has fully solved despite efforts to use active placebos or low-dose comparators.
The trial’s relatively small sample size compounds that concern. Phase IIa studies are designed to generate a preliminary efficacy signal, not to produce the kind of definitive evidence required for regulatory approval. The open-label second-dose component, while ethically sound, further complicates the data by removing the blinded comparison after the initial two-week assessment and introducing additional expectations among participants who know they are receiving the active drug. Researchers will need larger, independently replicated studies with more rigorous controls and longer follow-up to determine how much of the observed benefit is attributable to the pharmacology of DMT versus psychotherapy, expectancy, and other non-specific factors that can influence mood outcomes.
What Comes Next for DMT and Psychedelic Medicine
The SPL026 findings land in a rapidly expanding field of psychedelic research that spans psilocybin, MDMA, LSD analogues, and other compounds. Many of these studies are cataloged in databases such as the National Center for Biotechnology Information, where clinicians and scientists can review emerging evidence across different drug classes and psychiatric indications. Within that broader landscape, DMT’s unique selling point is its brevity: if subsequent trials confirm that a 10-minute infusion can deliver durable antidepressant effects, health systems may favor it over longer-acting psychedelics that are more resource-intensive to administer.
At the same time, the field is still in an exploratory phase. Investigators are experimenting with different dosing strategies, psychotherapy frameworks, and patient populations, and many maintain curated research profiles to track publications and collaborations. For DMT specifically, future work will need to clarify optimal patient selection, the value of one versus two infusions, and how best to integrate the acute psychedelic experience into ongoing care. Questions also remain about how DMT-assisted therapy compares with existing antidepressants, neuromodulation techniques, and other psychedelic protocols in terms of safety, efficacy, and cost-effectiveness.
Regulators and guideline committees will be looking for converging lines of evidence rather than isolated positive trials. Systematic reviewers are already assembling bibliographic collections of psychedelic studies to evaluate consistency of outcomes, risk profiles, and methodological quality. For SPL026, that means the promising phase IIa signal will need to be followed by larger, multicenter trials that test the drug in more diverse populations and real-world clinical settings. Only then will it be possible to know whether a single, short DMT infusion can reliably transform the treatment landscape for major depressive disorder or whether its benefits will prove more modest when scrutinized at scale.
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*This article was researched with the help of AI, with human editors creating the final content.
